The host response to invasive stimuli is characterized by profound physiological changes which lead to disruption of normal homeostatic mechanisms both locally and systemically. A number of well-characterized cytokines have been shown to elicit and control many of these changes. Four novel macrophage-derived mediators secreted in response to endotoxin challenge have now been purified to homogeneity, and biochemical and functional characterization initiated. These mediators are known, or suspected, to play a role in the host response to infection and injury. During the proposed grant period a coordinated, multifaceted program will allow further biochemical and functional characterization of these four mediators. The specific aims to firmly establish the inflammatory role of these monokines, to isolate cDNA clones for each for the dual purpose of studying cellular induction and distribution and producing recombinantly-derived material, and lastly to elucidate both in vitro and in vivo biological activities exhibited by each cytokine which contribute to the pathophysiology associated with invasive stimuli. Our long-term objectives are to define the mechanisms by which these four cytokines act alone, and in concert, to modulate inflammatory responses. Ultimately, this will provide the new understanding required to manipulate these hormonal influences to clinical advantage in the control of inflammatory and immune responses.